Delta-opioid receptor antagonists prevent sensitization to the conditioned rewarding effects of morphine.
BACKGROUND
Functional interactions between mu- and delta-opioid receptors (MOPr and DOPr, respectively) are implicated in morphine tolerance and dependence. The contribution of DOPr to the conditioned rewarding effects of morphine and the enhanced conditioned response that occurs after repeated morphine administration is unknown. This issue was addressed with the conditioned place preference procedure (CPP).


METHODS
Rats received home cage injections of saline or morphine (5.0 mg/kg/day x 5 days) before conditioning. For sensitization studies, DOPr antagonists (DOPr1/2: naltrindole, DOPr2: naltriben, DOPr1: 7-benzylidenenaltrexone) were administered before morphine injections. Conditioning sessions (2 morphine; 2 saline) commenced 3 days later. To assess the influence of acute DOPr blockade on the conditioning of morphine reward in naïve animals, 3 morphine and 3 saline conditioning sessions were employed. Antagonists were administered before morphine conditioning sessions.


RESULTS
Morphine was ineffective as a conditioning stimulus after two conditioning sessions in naïve rats. However, doses > or = 3.0 mg/kg produced significant CPP in morphine pre-exposed rats, confirming that sensitization develops to the conditioned rewarding effects of morphine. In animals that received morphine pre-exposure with naltrindole or naltriben but not 7-benzylidenenaltrexone, sensitization was prevented. No attenuation of morphine CPP was observed in animals that received DOPr antagonists acutely, before conditioning sessions.


CONCLUSIONS
These data indicate a critical role of DOPr systems in mediating sensitization to the conditioned rewarding effects of morphine. The efficacy of naltrindole and naltriben in preventing the enhanced response to morphine suggest the specific involvement of DOPr2 in the sensitization process.
Shippenberg
Toni S
TS
Integrative Neuroscience Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health/US DHHS, 333 Cassell Dr., Baltimore, MD 21224, USA. tshippen@intra.nida.nih.gov
Chefer
Vladimir I
VI
Thompson
Alexis C
AC
D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001597:Benzylidene Compounds / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects*; D004195:Disease Models, Animal; D008297:Male; D009021:Morphine Dependence / Q000503:physiopathology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012054:Reinforcement, Psychology; D018709:Statistics, Nonparametric
D001597:Benzylidene Compounds; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C068868:naltrindole benzofuran; C077358:7-benzylidenenaltrexone; D009271:Naltrexone; C055382:naltrindole